Pipeline News and Updates
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Only one investigational drug has an October 2019 PDUFA Date, Clinuvel Pharmaceutical’s afamelanotide (Scenesse). The FDA has given afamelanotide an Orphan Drug Priority Designation and its PDUFA Date is October 6, 2019. Afamelanotide is being developed as a treatment for erythropoietic protoporphyria. The drug is a melanocyte-stimulating hormone delivered via subcutaneous implant. Afamelanotide was approved in the EU in 2015. The FDA delayed the PDUFA date of afamelanotide for three months to allow more time for a full review of the NDA. In a 9-month, 74 patient, Phase III trial, patients treated with afamelanotide tolerated six hours of direct exposure to sunlight without pain compared to 0.8 hours with placebo in European patients with erythropoietic protoporphyria. In a 6-month, 94 patient, Phase III trial, patients treated with afamelanotide tolerated 69.4 hours of direct exposure to sunlight without pain compared to 40.8 hours with placebo in U.S. patients with erythropoietic protoporphyria. (N Engl J Med. 2015 Jul 2;373(1):48-59). There are no other late stage investigational drugs in our knowledgebase indicated for erythropoietic protoporphyria.
There is one investigational drug with a November 2, 2019 PDUFA Date, RedHill Biopharma’s combination of amoxicillin, omeprazole, rifabutin (Talcia). It is an oral combination product that has Fast Track and Qualified Infectious Disease designations for the eradication of H. pylori. The results of the Phase III ERADICATE Hp2 study have not been published, but Redhill announced that in the 455 patient trial, the combination of amoxicillin, omeprazole and rifabutin demonstrated an 84% eradication of H. pylori compared to 58% eradication with amoxicillin and omeprazole in dyspepsia patients with confirmed H. pylori infection. Regulatory Update
The FDA approved daily oral semaglutide (Rybelsus, Novo Nordisk) on 9/20/2019 for the treatment of Type 2 Diabetes. Novo plans to have a commercial insurance savings card program when Rybelsus is launched to reduce out of pocket costs to as little as $10 a month. WAC for a month’s supply of oral semaglutide is $772 (30 tablets) which is similar to 4 weeks of injectable semaglutide (Ozempic) at $770. The WAC for a month’s supply of injectable liraglutide is $920. Oral semaglutide was approved with a Black Box warning regarding a potential increased risk ofthyroid c-cell tumors. The drug is contraindicated for patients with a past history or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. The FDA has accepted the BLA enfortumab vedotin for the treatment of locally advanced or metastatic urothelial cancer and set a PDUFA date of 3/15/2020. The FDA has accepted the BLA for Merck’s Ebola vaccine for the prevention of infections with the Ebola virus and set a PDUFA date of 3/14/2020. Announced Research Updates Nanobiotix announced interim results from a Phase I/II trial, where 62.5% of hepatocellular carcinoma patients treated with NBTXR3 activated by stereotactic body radiation therapy (SBRT) have shown a complete response with the remainder demonstrating a partial response and 50% of patients with liver metastasis have shown a complete response with the remainder showing stable disease. Sage Therapeutics announced that in a 45-day, 150 patient, Phase II, trial, a daily oral dose of zuranolone decreased the Hamilton Rating Scale for Depression (HAMD-17) at 15 days by 17.8 points and by 19.2 points at 45 days compared to a 13.6 points decrease with placebo at 15 days and a 14.2 point decrease at 45 days in women with severe post-partum depression. MicuRx announced that in a 589 patient, Phase III trial, contezolid was non-inferior to linezolid (clinical cure 93% vs 93.4%) in Chinese patients with complicated skin and soft tissue infections. MicuRx is comparing contezolid to linezolid for the treatment of skin and skin structure infections in an ongoing U.S. Phase II trial. Published Research Updates In a 130-week, 120 patient, Phase II trial, patients were desensitized with a non-commercial peanut flour to tolerate 4000 mg of peanut protein. The patients were then assigned to no maintenance therapy, low dose peanut protein (300 mg) or placebo (oat flour) and retested. At 117 weeks the number of patients that passed a 4000 mg peanut protein challenge were 21/60 in the no therapy group, 19/35 in the low dose maintenance group and 1/25 in the placebo group. After 130 weeks the number of patients that passed the challenge test were 12/60 in the no therapy group, 15/35 in the low dose maintenance group and 1/25 in the placebo group. This suggested that discontinuation or a low dose maintenance after achieving a desensitization goal may result in patients losing their tolerance for the target peanut protein level. In the 26-week, 731 patient, Phase III Pioneer-8 trial, treatment with oral semaglutide lowered HbA1c 0.5% with 3 mg, 0.9% with 7 mg and 1.2% more than placebo and lowered body weight 0.9 Kg with 3 mg, 2 kg with 7 mg and 3.3 kg with 14 mg more than placebo in patients with type 2 diabetics. In a 38 patient, Phase III trial, treatment with galeterone did not improve radiographic progression-free survival compared with enzalutamide in patients with androgen receptor splice variant-7 (AR-V7) metastatic castration-resistant prostate cancer (mCRPC). In an 8-week, 14 patient, Phase II trial, treatment with serlopitant did not improve the itch numeric rating scale compared to placebo in patients with moderate-severe epidermolysis bullosa related pruritus. The FDA approved the weekly subcutaneous injection of semaglutide on 12/5/17 for the treatment of Type 2 Diabetes. Oral semaglutidewould be the first oral GLP-1 receptor agonist if approved. Oral semaglutide is being reviewed by the FDA and EMA and has a PDUFA date on 9/20/2019.
ICER released a draft analysis of semaglutidein September 2019. In estimating the net health benefit of semaglutide, ICER found the drug would potentially, but inconclusively provide a net health benefit compared to liraglutide, had low certainty of a benefit compared to empagliflozin, had moderate certainty of a benefit compared to sitagliptin and had a high certainty of a substantial net benefit when added to background therapy. ICER based its economic analysis for semaglutide on the cost of injectable semaglutide. A discount off WAC was used for semaglutide for an estimated annual cost of $6,520. Annual discounted prices used for comparators included $1,505 for sitagliptin, $2,088 for empagliflozin and $5,342 for liraglutide. The final market price would change the QALY analysis. Using these estimated costs, ICER estimated the incremental cost-effectiveness ratios for oral semaglutide as $100,000/QALY compared to liraglutide, $80,000/QALY compared to sitagliptin,and $160,000 compared to background treatment alone. Empagliflozin was found to be more cost-effective than semaglutide. The final ICER report on semaglutide is expected to be published on 12/9/2019. We provided a summary of the outcomes from the ten trial Phase III PIONEERtrials evaluating oral semaglutide for the treatment of type 2 diabetes in June of this year. Seven of the PIONEER trials have been published and The Pharmaceutical Pipeline Trackerhas links to PubMed abstracts and five more for a total of 12 semaglutide trials. The Knowledgebase also provides more detail on the primary outcome from each of the PIONEER trials. A subscription provides 24/7 access to the data. Regulatory Update
The FDA approved tenapanor (Ibsrela, Ardelyx) on 9/12/2019 for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults. The most common adverse event with tenapanor is diarrhea. The drug is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. The FDA designated Ridgeback Biotherapeutics’ mAb114 a Breakthrough Therapy for the treatment of Ebola. The FDA accepted the BLA forHorizon Therapeutics’ teprotumumabfor the treatment of active thyroid eye disease in September 2019 and set a PDUFA date of 3/8/2020, with an Orphan Drug Priority Designation. The FDA has accepted Allergan/Actavis/Molecular Partners’NDA and the EMA accepted the MAA for abicipar pegol for the treatment of neovascular age-related macular degeneration (wet AMD) in September 2019 with approval anticipated in mid to late 2020. The FDA's Allergenic Products Advisory Committee voted 7 –2in favoron efficacy and 8-1 in favor on safety for use of AR101 to reduce the incidence and severity of peanut allergy reaction in patients aged 4-7. It is likely AR101 will be approved with a REMS program that will require a prescription for epinephrine. Aimmune is considering pricing AR101 between $3,000 and $20,000 when the drug is approved. As a comparison, the current discounted price for grass and pollen allergy products is $5,000 a year.An FDA review of the drug found that despite both placebo and AR101 groups following a peanut avoidance diet, the AR101 group had an increased number of discontinuations, systemic allergic reactions and reports of eosinophilic esophagitis, but reduced the need for treatment after accidental exposure. Announced Research Updates Lilly announced interim data from the 105 patient, Phase I/II LIBRETTO-001, open-label trial, where treatment with selpercatinib resulted in a 68% overall response rate, a median duration of response of 20.3 months and progression free survival of 18.4 months in patients with RET fusion-positive non-small cell lung cancer, previously treated with platinum-based chemotherapy. Lilly plans to submit an NDA for Selpercatinib by the end of 2019 with potential approval in 2020. Axon announced that in the 24-month, 196 patient, Phase II, ADAMANT trial, treatment with AADvac1 resulted in a 12.6% decrease in Neurofilament Light Chain (a biomarker of neurodegeneration and neuronal loss) compared to a 27.7% decrease with placebo in patients with mild Alzheimer's Disease. Alnylam announced that in the six-month, 94 patient, Phase III, ENVISION trial, patients treated with givosiran had a mean annualized porphyria attack rate of 1.0 compared to 10.7 attacks with placebo in patients with acute hepatic porphyria. An open-label extension of the Envision trial enrolled 93 patients from the original trial where the reduction in the annualized porphyria attack rate with givosiran was sustained. Biogen and Eisai ceased development of elenbecestat in September 2019 after the drug’s independent monitoring board expressed concerns about safety. Biogen announced 18-month interim data from 888 patients enrolled in the 2-year, Phase III, open label, EVOLVE-MS-1 trial, where treatment with diroximel fumarate resulted in a 79.4% reduction in the annualized multiple sclerosis relapse rate in patients with relapsing-remitting multiple sclerosis, who previously received interferon or glatiramer acetate. Johnson & Johnson announced that in the 108-week, 1,133 patient, Phase III, OPTIMUM trial, treatment with ponesimod reduced the annualized relapse rate by 30.5% compared teriflunomide (0.202 vs 0.290) in patients with relapsing multiple sclerosis. Roche announced that in the 95 patient, Phase III, SAkuraStar trial, 76.1% of patients treated with satralizumab were relapse-free at 48 weeks, and 72.1% were relapse-free at 96 weeks compared to 61.9% at 48 weeks and 51.2% at 96 weeks with placebo in patients with NMOSD. Ritter announced that in a 61-day, 557 patient, Phase III trial, treatment with RP-G28 was no more effective that placebo in reducing symptoms of lactose intolerance (abdominal pain, cramping, bloating and gas). Published Research Updates In the 24-month, 1,320 patient, Phase III RADIANCE trial, treatment with Celgene’s oral ozanimod resulted in an annualised relapse rate of 0.17 with 1 mg and 0.22 with 0.5 mg compared to 0.28 with weekly intramuscular interferon beta-1a 30 mcg in patients with relapsing multiple sclerosis. In a 12-week, 249 patient, Phase II trial, 22.6% of patients that received Lilly’s mirikizumab 200 mg achieved remission compared to 4.8% with placebo in patients with moderate-to-severe active ulcerative colitis. The 230 patient, Phase III N-MOmentum trial was stopped early due to a clear demonstration of efficacy where treatment with Viela Bio/AstraZeneca’s inebilizumab resulted in 12% of the cohort experiencing aneuromyelitis opticaspectrum disorder (NMOSD) attack compared to 39% with placebo in patients with NMOSD. In a 180-day, 260 patient, Phase III trial, treatment with Mesoblast’s remestemcel-L did not improve the complete resolution of aGvHD symptoms for at least a 28 day period compared to placebo (35% vs 30%) in patients with steroid refractory aGvHD. In the 339 patient, Phase II, open-label, TRINITY trial, treatment with AbbVie’s rovalpituzumab resulted in an overall response rate of of 12.4% (with 14.3% in DLL3-high and 13.2% in DLL3-positive patients)and a median overall survival of 5.6 months in patients with DLL3-expressing small cell lung cancer in the third-line and beyond (3L+) setting.The drug has an Orphan Drug Priority Designation. In a 12-week, 71 patient, open-label trial, treatment with LGLife Sciences/Sanofi’s gemigliptin resulted in a 27.2 point decrease in the mean amplitude of glycemic excursions compared to a 7.9 point decrease with dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone or drug naive. In a 9.8-month, 70 patient, Phase II, open label, Chinese trial, treatment withBeiGene’stislelizumab resulted in an overall response rate of 87.1%, a complete response in 62.9% and a 9-month progression free survival rate of 74.5% in patients with relapsed or refractory Hodgkin's lymphoma. According to the American Cancer Society current worldwide research is focused on preventing, detecting and treating breast cancer. There are a total of eighteen investigational drugs in the Pharmaceutical Pipeline Tracker. Eight of the eighteen have FDA Priority Designations.
Using the Pharmaceutical Pipeline Tracker’s new Search for Priority Designation by Indication feature, you’ll find the current set of eight investigational drugs targeting breast cancer to which the FDA has given Priority Designations: entinostat (Syndax), lurbinectedin (PharmaMar), pelareorep (Oncolytics Biotech), sacituzumab govitecan (Immunomedics/ Seattle Genetics), tavokinogene telseplasmid (Oncosec Medical), trastuzumab deruxtecan (AstraZeneca/ Daiichi Sankyo), tucatinib (Cascadian Therapeutics), and veliparib (AbbVie). Although each have FDA Priority Designations, none have PDUFA Dates at this time. Here’s the latest on each from our News and Analysis section: Entinostat - Syndax is evaluating entinostat in combination with exemestane in a Phase III trial of patients with advanced hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+, HER2-) breast cancer. The drug has a FDA Breakthrough Therapy Priority Designation. Lurbinectedin - PharmaMar has a phase III lurbinectedin trials examining the change in progression-free-survival, overall survival and overall response rate in the treatment of platinum-resistant ovarian cancer and platinum-resistant small-cell lung cancers. Lurbinectedin has an Orphan Drug Priority Designation. Pelareorep - Oncolytics has an ongoing Phase II trial examining palareorep plus paclitaxel vs paclitaxel monotherapy in advanced/metastatic breast cancer. The drug has Fast Track and Orphan Drug Priority Designations. Sacituzumab govitecan – Although the FDA gave this investigational drug a Breakthrough Therapy Priority Designation in the treatment of triple negative breast cancer, the FDA rejected sacituzumab govitecan on 1/17/2019 due data integrity issues with manufacturing the drug. Immunomedics has an ongoing Phase III trial evaluating sacituzumab govitecan. Tavokinogene telseplasmid – The FDA has given this combination Fast Track and Orphan Drug Priority Designations. It provides a pulsed electrical field to cells from a hand-held applicator which temporarily increases the porosity of the cell membranes and allows DNA IL-12 to pass into the cell, which triggers production of IL-12 protein, which kills cancer cells by an immune response. Trastuzumab deruxtecan – this antibody drug conjugate has Fast Track and Breakthrough Therapy Priority Designations, is a HER2 targeting antibody drug conjugate with a humanized anti-HER2 antibody, cleavable peptide-based linker, and topoisomerase I inhibitor payload. Tucatinib - The FDA designate tucatinib an Orphan Drug. A Phase II trial of tucatinib in combination with capecitabine and/or trastuzumab in patients with metastatic HER2+ breast cancer is ongoing. Veliparib - Ongoing trials for veliparib include trials in patients with advanced BRCA-mutant, HER2-negative breast cancer and advanced, non-squamous NSCLC in current or former smokers. The FDA designate veliparib an Orphan Drug. Subscribe to the Pharmaceutical Pipeline Tracker to view the complete monographs of these eight and the other ten investigational drugs targeting breast cancer. Regulatory Update
The FDA accepted the BLA for inebilizumab in September 2019 for the treatment of patients with neuromyelitis optica spectrum disorder. The FDA accepted the NDA for voxelotor for the treatment of sickle cell disease in September 2019 and set a PDUFA date of 2/26/2020. The FDA designated capmatinib a Breakthrough Therapy for the treatment of metastatic MET exon14 skipping-mutated non-smallcell lung cancer. Announced Research Updates Ardelyx announced that in the 4-week, 236 patient Phase III, AMPLIFY trial, treatment with tenapanor plus a phosphate binder decreased serum phosphorus 0.84 mg/dL compared to a 0.19 mg/dL decrease with only the phosphate binder in dialysis patients with hyperphosphatemia not controlled by a phosphate binder regimen. Concertannouncedthat in a 24-week,149 patient, Phase II trial, treatment with CTP-543 resulted in achievement of a 50% reduction in the SALT score in 58% of patients with 12 mg, 47% with 8 mg and 21% with 4 mg compared to 9% with placebo in patients with moderate to severe alopecia areata. The 12 mg and 8 mg doses were significantly different from placebo, while the 4 mg dose did not achieve a significant difference. The Medicines Company announced that in the 18-month, 1,617 patient, Phase III, ORION-11 trial, the placebo adjusted reduction in LDL with inclisiran was 54% in patients with atherosclerotic cardiovascular disease or risk equivalents and elevated LDL despite maximum tolerated dose of statin with or without ezetimibe. AstraZeneca announced that in the 955 patient, Phase III, open-label, NEPTUNE trial, durvalumab plus tremelimumab did not improve overall survival compared to standard-of-care chemotherapy in patients with metastatic non-small cell lung cancer. Published Research Updates In the 12-month, 1,346 patient, Phase III SUNBEAM trial, treatment with oral ozanimod resulted in an annualised relapse rate of 0.18 with 1 mg and 0.24 with 0.5 mg compared to 0.35 with weekly intramuscular interferon beta-1a 30 mcg in patients with relapsing multiple sclerosis. In a 15-day, 89 patient, Phase II, trial, a daily oral dose of zuranolone decreased the Hamilton Rating Scale for Depression (HAMD-17) score by 17.4 points compared to a 10.7 point decrease with placebo in patients with major depressive disorder. Summary: In a busy August, the FDA approved seven new investigational drugsfor the marketplace,twice the monthly average of approvals for the first half of 2019. Four drugs in the Pharmaceutical Pipeline Tracker received new FDA Priority Designations. Two drugs hit bumps in the road with one rejection and one PDUFA Date delay. Seven drugs were involved with new NDA and BLA submissions. Finally, we’ve included two notable other developments. Read on.
Regulatory Approvals
Regulatory Update
The FDA approved istradefylline (Nourianz, Kyowa Kirin) on 8/27/2019 for the treatment of off episodes n adults with Parkinson's disease already receiving levodopa/carbidopa. Announced Research Updates AbbVie announced the early discontinuation of the small cell lung cancer MERU study after an interim analysis found that rovalpituzumab provided no survival benefit when used as a first-line maintenance therapy. AbbVie discontinued development of rovalpituzumab after discontinuation of the MERU trial. Esperion announced that in a 12-week, 179 patient, Phase II trial, treatment with bempedoic acid and ezetimibe lowered LDL-C by 40% more than ezetimibe monotherapy in patients with hypercholesterolemia and type 2 diabetes being treated with stable diabetes medication and washed out of lipid modifying therapy. MyoKardia announced 24-week interim data from 12 patient enrolled in the Phase II extension of the PIONEER-HCM trial (PIONEER-OLE), suggested that 10/13patients treated with mavacamten had improved their NYHA Classification of at least one class and 9/13 were asymptomatic and improvements in biomarkers were maintained at 36 weeks. Idorsia announced that in an 8-week, 430 patient, Phase II, dose ranging trial, treatment with aprocitentan lowered blood pressure 10.3/6.3, 15.0/9.9, 18.5/12.0 and 15.1/10.0 mmHg with 5, 10, 25, and 50 mg, compared to a decrease of 7.7/4.9 mmHg with placebo and 12.8/8.4 mmHg with lisinopril. Idorsia is evaluating aprocitentan in two Phase III trials, the PRECISION study in patients whose hypertension is uncontrolled by triple therapy and the INSPIRE-CKD study in patients with uncontrolled blood pressure and chronic kidney disease. Published Research Updates In a 272 patient, Phase I/II, dose escalation, open-label trial, treatment with olmutinib resulted in an overall objective response rate of 55.1% in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy. In a 24-week, 226 patient, dose ranging, Phase II trial, patients treated with nemolizumab 30 mg sub-q every four weeks reduced the Eczema Area and Severity Index score by 68.8% compared to a 52.1% decrease with placebo in in patients receiving topical corticosteroids with moderate-to-severe atopic dermatitis, severe pruritus and inadequate control with topical treatment. The 10 mg and 90 mg doses of nemolizumab did not perform as well against placebo at 24 weeks and may not have reached statistical significance. In a 19 patient, Phase II open-label trial, treatment with 6 months of talazoparib prior to surgery resulted in a residual cancer burden pathologic complete response (RCB-0) rate of 53% and RCB-0/I of 63% in patients with germline BRCA pathogenic variant (gBRCA-positive) and operable breast cancer. In an extension of a 1,046 patient, 3-dose, Phase II, trial, 116 patients received a booster dose of Sanofi’s dengue vaccine 5-6 years after completing the initial dosing series and achieved serotype titers that were similar to titers reached after the third dose of the initial series. In a 17 patient Phase I, open label trial, treatment with enfortumab vedotin resulted in a 35.3% objective responserate in Japanese patients with locally advanced or metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin. In a 45 patient, Phase II, open label trial, pracinostatadded to hypomethylating agents did not improve outcomes in patients with myelodysplastic syndrome that did not respond to hypomethylating agent therapy. In a 6-week, 580 patient, Phase III trial, patients that received a daily blonanserin transdermal patch decreased their PANSS score 5.6 points with 40 mg and 10.4 points with 80 mg compared to placebo in Japanese patients with acutely exacerbated schizophrenia. In a 32-patient, Phase II, open-label trial, treatment with quizartinib resulted in complete remission in 53.8% of patients with a median duration of 16.1 weeks and overall survival of 34.1 weeks in Japanese patients with FLT3-ITD positive relapsed/refractory AML. |
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